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Risk stratification in cardiovascular disease primary prevention scoring systems, novel markers, and imaging techniques

Risk stratification in cardiovascular disease primary prevention – scoring systems, novelmarkers, and imaging techniques Faiez Zannada*, Guy De Backerb, Ian Grahamc, Matthias Lorenzd,Giuseppe Manciae, David A. Morrowf, Zˇeljko Reinerg, Wolfgang Koenigh,Jean Dallongevillei, Robert J. Macfadyenj, Luis M. Ruilopek, Lars Wilhelmsenl, the ESC Working Group on CardioVascularPharmacology and Drug TherapyaCentre for Clinical Investigation, Institut Lorrain du Coeur et des Vaisseaux, CHU Brabois, 54500 Vandoeuvre, FrancebDepartment of Public Health, Ghent University, De Pintelaan 185, Gent B-9000, BelgiumcDepartment of Cardiology, Adelaide and Meath Hospital, Tallaght, Dublin 24, IrelanddDepartment of Neurology, Frankfurt University, Frankfurt D-60528, GermanyeDivision of Internal Medicine, University of Milan-Bicocca, Monza, Milan, ItalyfDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA gUniversity Hospital Center, School of Medicine, University of Zagreb, Salata 2, 10 000, Zagreb, CroatiahDepartment of Internal Medicine II Cardiology, University of Ulm Medical School, Robert-Koch Str 8, D-89081, Ulm,GermanyiDepartment of Epidemiology and Public Health at Pasteur Institute of Lille, 1 rue du Pr. Calmette, BP 245, F-59019,Lille Cedex, FrancejUniversity Department of Medicine, City Hospital, NHS Trust, Dudley Road, Birmingham B18 7QH, UKkHypertension Unit, 12 de Octubre Hospital, Madrid 28041, SpainlDepartment of Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden Clinical
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The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009.
Classical risk factors such as blood pressure and low-density lipoprotein cholesterol Fundam
levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-riskratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even witheffective control of dyslipidemia and hypertension. Novel measures include C-reactive *Correspondence and protein, lipoprotein-associated phospholipase A2, genetic markers, and markers ofsubclinical organ damage, for which there are varying levels of evidence. High-resolution ultrasound and magnetic resonance imaging to assess carotid atheroscle-rotic lesions have potential but require further validation, standardization, and proofof clinical usefulness in the general population. In conclusion, classical risk scoringsystems are available and inexpensive but have a number of limitations. Novel riskmarkers and imaging techniques may have a place in drug development and clinicaltrial design. However, their additional value above and beyond classical risk factorshas yet to be determined for risk-guided therapy in CVD prevention.
ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutiqueFundamental & Clinical Pharmacology 26 (2012) 163–174 [7]. This association was present in men and women, old and young, and in all ethnic groups throughout the world.
To date, decisions regarding drug therapy for the The Systematic COronary Risk Evaluation (SCORE) prevention of cardiovascular disease (CVD) have relied project was initiated by the ESC to develop a system of risk on the assessment of classical risk factors to identify estimation for clinical practice in Europe [8]. The subjects who may be candidates for the initiation and resulting risk stratification SCORE is based on a very optimization of therapy. Currently, drugs such as statins large data set that is representative of European popula- are mainly prescribed according to low-density lipopro- tions. Charts for high- and low-risk countries increase its tein cholesterol (LDL-C) level, antihypertensive drugs are applicability, and the chart can be recalibrated with local prescribed according to blood pressure (BP) levels, and mortality data. Currently, SCORE is not applicable for therapeutic targets are adjusted for additional risk (e.g., people <40 or >70 years of age. However, a relative risk the presence of concomitant diabetes). The latest inter- chart is available to show younger people with dyslipi- national guidelines have refined this approach by inte- demia or high BP that they are at increased lifetime risk grating total risk assessment for individual patients in for CVD, relative to others in their age group [3,9].
therapeutic decision making [1–3]. The recent European Such systems need to be simple if general physicians Medicines Agency (EMEA) guideline on medicines for the are to be encouraged to use them. Risk scoring systems prevention of CVD will allow drugs to be indicated on the need to improve the detection of young to middle-aged basis of risk scores [4]. On the other hand, recent people with a low 10-year risk for CVD, but a moderate– research has led to improved appreciation of pathophys- high lifetime risk, so that they can benefit from early iology that may be translated into improved diagnosis, interventions such as lifestyle modification that aim to prediction, prognostication, and risk subclassifications.
prevent progression to the high-risk group in later life.
Newer risk assessment tools may permit earlier and more This is an area where newer assessments, such as targeted intervention. The present paper reviews cur- inflammatory markers or carotid intima-media thickness rently available methods of risk stratification, as well as (cIMT), might be used to reclassify people. The Reynolds emerging biomarkers and imaging techniques.
Risk Score is a recently developed scoring system that This is one of two reports based on the results of incorporates a range of traditional and novel risk discussions that took place during a special CardioVas- markers, and was shown to reclassify 40–50% of women cular Clinical Trialists (CVCT) workshop organized by at intermediate risk (according to ATP III prediction the European Society of Cardiology (ESC) Working Group scores) into higher- or lower-risk categories [10]. The on Cardiovascular Pharmacology and Drug Therapy in addition of high-sensitivity C-reactive protein (hsCRP) September 2009. The manuscript has subsequently been and parental history to the Reynolds Risk Score reviewed and updated by all authors. The other report, significantly improved cardiovascular risk prediction in ‘Prevention of CVD guided by total risk estimations – challenges and opportunities for practical implementa- Using data from participants in the Framingham Heart tion’, was published online in September 2011 [5].
Study, Lloyd-Jones and colleagues [12] estimated thatthe life-time risk of developing coronary heart disease(CHD) at age 40 in a general population was one in two D E V E L O P M E N T S I N C A R D I O V A S C U L A R for men and one in three for women. They suggested that this knowledge should promote efforts toward the For many years, there has been a belief in cardiology that detection and treatment of individuals at increased risk.
only half of the variance in CVD incidence can be The highest risk for CVD events is at the highest risk explained through classical risk factors, including poten- factor levels, which explains the intensive targeting of tially modifiable factors such as smoking, diabetes, BP, patients in this category – the ‘high-risk approach’.
and LDL-C levels, and two of the greatest (but non- However, a large number of events occur in the many modifiable) risk predictors, age and sex [6]. In fact, most of people at moderate risk, who may also benefit from the between-population and between-individual variance preventive actions – the ‘population approach’. The in CVD can be explained by classical risk factors. In the importance of these two approaches, which are comple- INTERHEART study, for example, nine potentially mod- mentary, was emphasized by Rose [13]. The population ifiable risk factors account for over 90% of the risk of strategy in preventive cardiology involves primarily experiencing an initial acute myocardial infarction (MI) community-oriented activities focusing on the whole ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 26 (2012) 163–174 population or subgroups. It is mainly concerned with Blood Institute definition of metabolic syndrome in 2005 health promotion, legislation, and primary prevention of [16]. The optimal glucose level has yet to be established, the development of risk in the young [14]. That is, the however, and hemoglobin A1c (HbA1c) may be a better aim is to ensure that healthy children preserve their ideal measure of risk than IFG or impaired glucose tolerance.
cardiovascular risk levels as they grow into adulthood.
In individuals at high risk of diabetes but with normal The high-risk concept mirrors the clinical approach to glucose tolerance, a clear association has been demon- patients, and the scoring systems may indicate when to strated between elevated HbA1c (‡6.5%) and increased prescribe drugs. The intensity of the approaches should all-cause mortality [17]. In another recent study, be adapted to the total cardiovascular risk of the subject.
non-diabetic hyperglycemia, assessed either by fasting However, the cut-offs for drug treatment vary with the glucose categories or continuously by HbA1c, was available evidence for risk-to-benefit ratios and cost- shown to correlate with both prevalence and severity effectiveness of drugs. In secondary prevention, as well as when end-organ damage is present, the CVD risk is Overall, one may conclude that the merits of the elevated above that predicted based on the usual risk classical risk factors outweigh their limitations. The factors and drug treatment is generally valuable.
problem facing the implementation of CVD prevention Other potential limitations of classical risk factors is not the need for more personalized treatment but the include their use in isolation – the ‘single risk factor failure to act in those with the potential to benefit. New approach’. Separate guidelines on hypertension, diabe- clinical trial data would be required to support a SCORE- tes, or dyslipidemias have this limitation; that is, they guided new indication, which may limit opportunities to may mention other risk factors but the focus is on just use older, generic drugs that are so far being prescribed one risk factor, which may be misleading. Nevertheless, based only on levels of individual risk factors. Many basing treatment decisions on separate single risk factors health insurance organizations will only reimburse such as initiating antihypertensive treatment based on statins and antihypertensive agents for patients with at BP and statins based on LDL-C levels has been shown to least a 20% 10-year Framingham risk of CVD. As a result, be effective. However, the assessment of classical risk people with a risk score <20% may not be treated, even factors may be imprecise. For example, characterizing a though they are still at increased risk. For example, an given subject by a single measurement of BP, LDL-C, or analysis of data from US national surveys conducted glucose levels, does not take into account either regres- approximately a decade apart showed barely any change sion-dilution bias, biological variation over time or in the distribution of 10-year risk of developing CHD [19].
measurement errors. In most epidemiological cohortstudies in the past, a risk factor was measured once at E M E R G I N G B I O M A R K E R S A N D baseline, providing a single snapshot, and the cohort was then followed over time. However, lifelong exposure tomost of the classical risk factors is not static but dynamic.
The Anglo-Scandinavian Cardiac Outcomes Trial – Lipid As a result, risk scores based on single one-time Lowering Arm (ASCOT-LLA) demonstrated that treat- measurement data may be inaccurate. Therefore, one ment of patients with indicators of subclinical CVD could should try to perform long-term studies with multiple reduce cardiovascular events [20]. New markers may measurements, and as precisely as possible, in order to contribute to reclassification of risk in some individuals, achieve a clearer understanding of the true relationship particularly those currently considered at intermediate between the risk factor and the incidence of CVD.
risk based on classical scoring systems. Such cases may be Finally, no matter how well we control dyslipidemia reclassified as low risk, minimizing the need for interven- and hypertension, residual risk remains in a proportion tion, or upgraded to high risk, allowing initiation of more of patients because of the presence of other risk factors, intensified therapeutic strategies [10,11]. Few of these some of which [e.g., low levels of high-density lipoprotein markers have been subjected to appropriate testing with cholesterol (HDL-C)] may be modifiable with appropriate respect to their additional value using post-test risk management [15]. Patients with the metabolic syn- calculations based on likelihood ratios, net reclassification drome or diabetes are known to be at increased risk of improvement, and integrated discrimination [21].
early onset coronary artery disease (CAD). As a result, Potential indicators of subclinical disease that may impaired fasting glucose (IFG) was incorporated in the allow targeted preventive therapy include biomarkers American Heart Association/National Heart, Lung and ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutiqueFundamental & Clinical Pharmacology 26 (2012) 163–174 techniques, and indicators of end-organ damage [22]. To date, however, there are few randomized trials that have Atherosclerosis has the characteristic features of a directly examined specific interventions to modify the chronic inflammatory process, from lesion initiation to risk associated with these indicators.
plaque rupture. It is also characterized by a low-gradesystemic inflammatory response that can be measured by high-sensitivity assays focusing on a large array of Despite the limited value of LDL-C in predicting future different candidate molecules. In most cases, well- cardiovascular events [23], the most important inter- controlled, large, prospective epidemiological studies vention to combat atherosclerosis in both primary and have been conducted that demonstrate an association secondary prevention is the prescription of statins which, between elevated levels of these inflammatory biomar- depending on their dose, can profoundly lower LDL-C.
kers and various cardiovascular outcomes [36]. It is Numerous studies have demonstrated a 25–44% relative therefore possible that these markers may not only be risk reduction for major cardiovascular events with the used for improved risk stratification but may also serve use of statins. Nevertheless, it is clear that residual risk as markers for the diagnosis of acute or chronic remains in many patients, including some of those who syndromes, early detection of subclinical disease, mon- achieve their LDL-C goals [24]. Measurement of apoli- itoring of disease progression, choice of therapy, and poprotein B (apoB) levels has been suggested as a potential response to therapy. So far, however, the potentially useful means of improving cardiovascular clinical utility of all these markers remains controversial.
risk assessment, as apoB is a key component of all the Besides the classical risk factors, such as LDL-C and atherogenic lipoprotein particles [25]. A number of HDL-C, the largest database exists for hsCRP, the studies, such as INTERHEART [26], the Apolipoprotein classical acute phase reactant, and lipoprotein-associated Mortality Risk (AMORIS) study [27], and the Air Force/ phospholipase A2 (Lp-PLA2). Lp-PLA2 is a member of the phospholipase A2 family that plays an important role in (AFCAPS/TexCAPS) [28] indicated that apoB had a issues related to oxidative stress in the blood vessel wall.
higher predictive value than LDL-C for coronary risk.
Increases in both hsCRP and Lp-PLA2, based on either However, other studies have not shown such a benefit enzyme levels or activity, are associated with various with apoB [29–31] and the assay is not yet widely adverse cardiovascular outcomes, including non-fatal available. Furthermore, endpoint trial data based on and fatal CHD and stroke [37,38]. The latter is an apoB as opposed to LDL-C are lacking, and the use of intriguing finding, as the most important laboratory apoB as a major risk marker would necessitate revision value used to assess cardiovascular risk, LDL-C, is not of all guidelines concerning cardiovascular risk stratifi- significantly associated with incident stroke [39].
HsCRP represents the first inflammatory biomarker Several studies and meta-analyses have suggested that that fulfills most, if not all, of the phases defined by the non-HDL-C might provide an even better estimation of American Heart Association as necessary for the eval- risk than LDL-C, particularly in patients with elevated uation of a novel biomarker [40]. That is, hsCRP triglycerides, diabetes and/or metabolic syndrome, as concentrations differ between subjects with and without well as in patients with chronic kidney disease [32]. In adverse outcome (phase 1); hsCRP predicts the develop- these populations, therefore, non-HDL-C may be recom- ment of future outcomes in multiple prospective cohorts mended as a useful risk marker [23].
and nested case cohort studies (phase 2); hsCRP adds Elevated levels of lipoprotein(a) [Lp(a)] have also been predictive information to established, standard risk shown to be associated with increased cardiovascular markers such as lipid levels and Framingham Risk Score risk, with no threshold or dependence on LDL-C levels (FRS), in some, but not all studies (phase 3); and, as [33]. There is also strong evidence that genetic determi- demonstrated in Justification for the Use of Statins in nants of Lp(a) level are associated with increased risk of Prevention: an Intervention Trial Evaluating Rosuvast- CAD [34,35]. The European Atherosclerosis Society atin (JUPITER) [41] has the potential to alter the Consensus Panel has therefore recommended screening predictive risk sufficiently to change the recommended for Lp(a) in intermediate- or high-risk patients, and the therapy (phase 4). Use of hsCRP as a risk marker to guide use of niacin to achieve a target level of <50 mg/dL [33].
statin therapy actually improved clinical outcomes in There are, however, no outcome trial data to support this JUPITER (phase 5). Furthermore, the low number needed to treat for the primary combined endpoint projected ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 26 (2012) 163–174 over 5 years in the JUPITER trial – 25 patients – justified arteries. sPLA2 is a known activator of inflammatory the additional costs of testing and treatment (phase 6).
processes and has been shown to have additive prog- Finally, the reduction in the incidence of the primary nostic value to traditional risk factors for CAD [52].
endpoint in JUPITER was greater than predicted by LDL- There are fewer data on sPLA2 compared with either C reduction alone, and patients who achieved the lowest Lp-PLA2 or hsCRP, but a phase II trial, Phospholipase level of hsCRP also had the greatest benefit in terms of Levels And Serological Markers of Atherosclerosis II risk reduction. While there has been considerable critical (PLASMA II), showed that use of an inhibitor of sPLA2 debate on the clinical relevance of the JUPITER findings (varespladib) reduced LDL-C, non-HDL-C and very-LDL and, indeed, questions raised about the impartiality of particle concentrations significantly compared with pla- the investigators [42], Ridker and Glynn [43] have cebo in statin-treated patients with CHD [53]. A phase III published a clear refutation of these arguments. Never- trial, Vascular Inflammation Suppression to Treat Acute theless, the omission of a low hsCRP group from this Coronary Syndrome (VISTA-16, http://www.clinicaltri- trial, and the fact that the cases were relatively high risk, NCT01130246), is currently underway to eval- mean that further investigation may be necessary to uate the efficacy of varespladib compared with placebo clarify the role of hsCRP as a risk marker.
(in addition to standard care) in terms of cardiovascular Based mainly on evidence from JUPITER, the US Food event rates in patients with acute coronary syndrome.
and Drug Administration (FDA) has recently approvedrosuvastatin for the prevention of MI and stroke in patients with healthy cholesterol levels but high levels of hsCRP[44]. The question now is in which population hsCRP Genes hold permanent information that may be infor- testing might be indicated, although recent American mative about disease processes. For example, different College of Cardiology Foundation/American Heart Asso- genetic abnormalities are responsible for familial hyper- ciation guidelines have given hsCRP a class IIa (JUPITER cholesterolemia (FH) and familial defective apoB-100, criteria) and class IIb (intermediate risk) indication for even though the two conditions are phenotypically testing [45]. The FDA requires at least one additional risk similar. Furthermore, lifelong exposure to the conse- factor, besides the JUPITER entry criteria of age and quences of a genetic abnormality may also influence elevated hsCRP level, to define eligibility for treatment disease processes (e.g., exposure to elevated LDL-C in with rosuvastatin. Opinion in Europe is somewhat differ- patients with FH). The association of single genes with ent to the US. In keeping with its guideline on medicines for specific diseases is now well established scientifically and the prevention of CVD [4], the EMEA has taken a different in clinical practice, but multiple gene models of disease approach and has recently extended the label of rosuvast- are still a prospect for the future. ‘Omics’ (e.g., genomics, atin to primary prevention based on risk scoring rather transcriptomics, proteomics) may be more informative at the population level than at the individual level. For Lp-PLA2 is an enzyme that resides in the blood vessel example, common genetic variants may have a small wall and generates pro-inflammatory and pro-athero- effect on the individual, but their impact at the popula- genic products, such as oxidized free fatty acids and lysophosphatidylcholine from its substrate, oxidized LDL.
Heritability of CVD and cardiovascular risk factors is There is compelling evidence from immunohistochemical the result of both environmental and genetic factors as studies in the coronary and cerebrovascular beds that well as an interaction of the two. There is evidence of increased deposition of Lp-PLA2 – particularly in the strong heritability of many phenotypes involved in CVD, plaque core – is associated with more advanced athero- including dyslipidemia, hypertension, diabetes, obesity, sclerotic disease [47–49]. However, only adequately and metabolic syndrome. First-degree relatives of affected powered randomized clinical trials like STABILITY patients should therefore be screened for their relevant ( [50] and SOLID ( A number of genetic polymorphisms (sequence vari- =NCT01000727) [51] can establish the potential of ants that occur at a frequency of >1%) appear to be Lp-PLA2 inhibition in addition to standard of care treat- associated with statistically significant effects on risk.
Because of the polygenic and polyfactorial determinants Secretory phospholipase A2 (sPLA2) is another enzyme of the most common CVDs, the effect of single polymor- that is expressed in both normal and atherosclerotic phisms is rather modest. So far, therefore, DNA-based ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutiqueFundamental & Clinical Pharmacology 26 (2012) 163–174 tests do not add significantly to diagnostic utility, better sures (e.g., calculation of glomerular filtration rate, risk prediction, or patient management. Nevertheless, microalbuminuria, electrocardiographic left ventricular several studies have identified genetic variants that are hypertrophy [LVH], and serum creatinine) make use of associated with increased risk of individual risk factors, procedures so simple and inexpensive that they can be CAD, or stroke [54–57]. As a result, commercial testing proposed for routine use. Others (e.g., echocardiograph- is now available to predict an individual’s genetic risk, ically detected LVH or atrial dilatation, ultrasonographic including direct-to-consumer testing, even though the evidence of carotid artery thickening or plaques, arterial clinical benefits of testing have not yet been demon- stiffening as shown by an increased velocity of pulse strated [58]. In some rare conditions, the process of wave transmission from central to peripheral arteries, genetic counseling can be optimized and extended with and low ankle/brachial BP ratio) add important infor- cascade screening, which leads to the identification of mation, but their limited availability in clinical practice subjects at risk and timely treatment of affected relatives.
mean they are used mainly as back-ups to routine FH is a good example of this [59]. However, the value of measurements. Routine or back-up measurements, genotyping, as compared with phenotyping, for better however, should be used to explore the status of management of risk and prevention in relatives has not different organs because multiple organ damage carries a worse prognosis than single organ involvement Transcriptomics is the analysis of multiple gene products to allow the identification of markers that In individuals with one or more classical risk factors, may provide information about the biological processes who do not appear to have a high total cardiovascular underlying disease. This type of study may reveal risk according to current methods of quantification, multiple networks of genes and proteins that interact subclinical organ damage is common. In the Assessment together to promote normal physiological processes.
of Prognostic Risk Observational Survey (APROS), more Classical markers of CVD risk, such as expression of the than 50% of the hypertensive patients defined as being at LDL-C receptor, can also be detected in this way.
low-to-moderate risk by the usual methods had to be Currently, genomics/transcriptomics can inform the reclassified as being at high risk after echocardiography design of scientific studies to understand disease mech- and carotid ultrasonography-detected LVH or arterial anisms, but they are not appropriate for risk stratifica- thickening or plaques [63]. Moreover, there is evidence tion. A genetic variant that is not very common in the that changes in some measures of subclinical organ general population might, nevertheless, have a large damage, such as proteinuria, microalbuminuria, elec- impact within specific families, and could influence trocardiogram (ECG) findings, or echo- or ECG-detected treatment decisions for such groups. This is an area that LVH, correlate with long-term risk of a cardiovascular is attracting a lot of commercial interest at present.
event [64,65]. These measures thereby provide informa- Genomics/proteomics might be used in the future to tion on whether or not the selected treatment is actually identify patients who will benefit from specific drugs and/ or to explain variability in patient responses to particular Finally, assessment and management of subclinical organ damage may help to reduce the high residual riskthat characterizes even apparently appropriate treatmentof cardiovascular risk factors [2]. That is, the inability to M E A S U R E S O F S U B C L I N I C A L O R G A N normalize total cardiovascular risk in many cases may be due, at least in part, to the fact that treatment is started too The assessment of subclinical organ damage can dem- late, when organ damage is already irreversible. Several onstrate whether or not the existing risk profile has lines of evidence support this view, including data already led to abnormalities in the structural and obtained in the Pressioni Arteriose Monitorate E Loro functional properties of vital organs that, although Associazioni (PAMELA) study [66]. In this population, the clinically silent, increase the chance of a future clinical prevalence of echocardiographic LVH was found to be event. Several measures of organ damage with clear-cut lower among treated hypertensive patients in whom BP long-term prognostic significance have been identified was controlled (office, home, and ambulatory values) than and can be proposed for practical use.
in those in whom it remained uncontrolled. The residual According to the European Society of Hypertension/ prevalence, however, was much greater than that of truly ESC hypertension guidelines [1,2], some of these mea- ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 26 (2012) 163–174 High-resolution ultrasound imaging of cIMT and For a general use of carotid ultrasound as a tool for risk classification and practical management of patients, The independent prognostic value of cIMT and carotid more studies in the general population and in risk plaques for the prediction of MI, stroke, and death has cohorts are needed with state-of-the-art statistics [78].
been demonstrated in several large studies [67–72]. The However, a meta-analysis of 41 trials found no relation- absolute event risks that can be predicted by cIMT ship between cardiovascular drug-induced regression or assessment in general populations of men were 1.3% per slowed progression of cIMT and a reduction in cardio- year for stroke [73] and 2.3% per year for MI [74]. The vascular events [79]. Another meta-analysis project absolute event risks in a cohort with maximum carotid (USE-cIMT, under the supervision of Michiel Bots, plaque thickness ‡1.9 mm was 3.5% per year for a Erasmus Medical Center, Rotterdam, Netherlands) is combined endpoint of stroke, MI, and vascular death underway to pool individual data from a series of large [66]. In populations with known risk factors, higher absolute risks may be predicted by the presence of In summary, carotid ultrasound can identify target increased cIMT and carotid plaques. However, compared organ damage in patients with risk factors for athero- with conventional risk stratification tools, such as the sclerosis. Early detection of increased cIMT or plaque FRS or SCORE models, the effectiveness of cIMT and lesions and initiation of cardioprotective therapy may plaques in terms of absolute risk prediction seems limited improve outcomes, but this needs to be investigated in prospective studies of asymptomatic patients at moderate For the criterion of improved risk classification, only a risk for CVD. Carotid ultrasound may assist in the initial few data sources are available to date. A study of 286 risk assessment of patients and in treatment decisions, patients with dyslipidaemia compared the risk classifica- but it is not yet appropriate for routine monitoring of tion by the FRS and by maximum cIMT [75]. Patients with intermediate risk for cardiovascular events (1–2%per year on FRS) and cIMT above the (post-hoc defined) cut-off were found to have an actual event rate of ‡4% Coronary artery calcification (CAC) is a recognized per year, demonstrating better risk classification with characteristic of atherosclerosis. In 2000, an American cIMT than with conventional risk factors alone [69]. In a College of Cardiology/American Heart Association con- general population sample of 13 145 healthy subjects, sensus document assigned a Class IIb recommendation the addition of cIMT to a risk model modestly improved for the use of CAC assessment by cardiac computed risk prediction and reclassified individuals primarily in tomography to improve cardiovascular risk assessment the intermediate- and high-risk groups [76]. In the in intermediate-risk patients [80]. In a review of Northern Manhattan Study, in which the majority published prospective studies using non-invasive meth- (63%) of the population was Hispanic, subjects with ods to detect subclinical atherosclerosis, Simon et al.
carotid plaque thickness ‡1.9 mm yielded absolute risks [81] reported that both CAC and carotid plaque were of >24% in 10 years for stroke, MI, or vascular death, ‘excellent’ for predicting CHD, while the other measures irrespective of their FRS classification [72].
evaluated (cIMT, ankle-arm index and aortic pulse wave More recently, in the general population, the incre- velocity) were only ‘fair’ (Table I) [81].
mental predictive value of cIMT has been questioned A more recent review of the evidence also confirmed based on results from the Carotid Atherosclerosis that baseline CAC identifies coronary atherosclerosis, and Progression Study (CAPS) [77]. After a 10-year follow- that progression of CAC is associated with increased risk of up of 4904 subjects without pre-existing vascular cardiovascular events [82]. However, the authors noted disease, cIMT was predictive for cardiovascular end- that there is currently little evidence that any therapeutic points. However, compared with a model using the interventions can slow the progression of CAC. They Framingham or the SCORE risk factors, a model that therefore suggested that quantification of CAC progression included the cIMT did not consistently improve the risk should not yet be recommended in routine clinical practice. The uncertainty surrounding the benefits or Studies including larger numbers of subjects from otherwise of CAC screening has been highlighted by two other ethnic backgrounds are needed to demonstrate recent publications, one of which (a prospective random- whether or not these results are generalizable to non- ized trial) found that CAC scanning was beneficial in terms of CAD risk factor control [83], and the other (a ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutiqueFundamental & Clinical Pharmacology 26 (2012) 163–174 Table I Criteria for choosing subclinical atherosclerosis test. (Reprinted from Simon A et al. Comparative performance of subclinical atherosclerosis tests in predicting coronary heart disease in asymptomatic individuals. Eur. Heart J. (2007) 28 2967–2971 by permission of cIMT, carotid intima-medica thickness; PWV, pulse wave velocity.
meta-analysis) reported limited evidence of benefit [84]. On cost of the investigation, there is still a long way to go the other hand, for clinical decision making, the association before clinical utility in terms of risk stratification.
of CAC and event rates within conventional risk categoriescould be important to reclassify subjects appropriately. It may be used beneficially in intermediate-risk subjects, inwhom the required intensity of therapy for risk factor Current risk scoring systems for CVD prevention are modification is currently uncertain. In this category, a available, inexpensive, and useful but may misclassify high CAC identifies subjects at high risk, in whom individuals with multiple and/or confounding factors.
intensive treatment of risk factors may be warranted [85].
Most novel risk markers have yet to be evaluated incomparison with, and in the context of, classical riskfactor scoring systems. Their role in risk-guided therapy M A G N E T I C R E S O N A N C E I M A G I N G O F for CVD prevention therefore remains uncertain. How- C A R O T I D A T H E R O S C L E R O T I C L E S I O N S ever, such markers may prove valuable for reclassification In recent years, magnetic resonance (MR) imaging of risk in patients with non-classical risk factors. At techniques have been developed to identify unstable, present, one potential application for emerging biomar- ‘vulnerable’ plaques. These techniques have shown good kers and imaging strategies is to guide drug development results in patho-histological validation studies, with and clinical trial design. For example, trials could combine reproducibility ranges between substantial and very measurement of hsCRP to assess global risk and imaging good [86] where assessed. Clinical validation data are to identify the extent of atherosclerotic disease. Such sparse [87,88] but promising. Before clinical application, studies might be useful for assessing potential new however, standardization, assessment of reproducibility, therapies, adding evidence to support a go/no go decision, proof of independent prediction of events and of clinical before a large commitment is made to execute a cardio- usefulness in terms of reclassification will be needed. MR vascular endpoint study. However, there is insufficient imaging of carotid plaques is expensive and, while it may evidence to support biomarkers or imaging as primary become useful to improve selection of subjects for carotid endpoints for phase III evaluation of new drugs. Ongoing surgery or stenting, it is unlikely to be useful in the large studies, such as the BioIMAGE study (http:// context of risk stratification in primary prevention. NCT00738725), should provideadditional information about the value of biomarkers andimaging techniques for risk assessment and treatment C O R O N A R Y M A G N E T I C R E S O N A N C E decisions. In the interim, we should aim to improve adherence to guidelines for the prevention of CVD, leading Given the tremendous technical difficulties of displaying to better management of known risk factors.
the coronary arteries with MR angiography with sufficientprecision to classify coronary stenoses, the performance of contemporary MR techniques is impressive. However, theprecision of these methods, validated against angiogra- The statements in the manuscript are based on the phy, is limited: either sensitivity or specificity does not results of discussions that took place during a special exceed 60–70% [89–91]. Given these limitations and the CardioVascular Clinical Trialists workshop organized by ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 26 (2012) 163–174 the European Society of Cardiology Working Group on on a Clinical Events Committee from AstraZeneca; CardioVascular Pharmacology and Drug Therapy in research grant support to Brigham & Women’s hospital September 2009, with the following faculty: Christie from AstraZeneca, Bayer Healthcare, Beckman Coulter, Ballantyne (Houston), Pascale Benlian (Paris), Corine Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Co, Bernaud (Brussels), Stefan Blankenberg (Mainz), Jan GlaxoSmithKline, Merck and Company, Nanosphere, Buch (Copenhagen), Alberico Catapano (Milan), Renata Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Cifkova (Prague), Jean Dallongeville (Lille), Guy De Pfizer, Roche Diagnostics, Sanofi-Aventis, Siemens, and Backer (Ghent), Ian Graham (Dublin), Javier Jimenez Singulex. Zˇeljko Reiner received honoraria as a speaker (Brussels), Wolfgang Koenig (Ulm), Matthias Lorenz from Solvay, MSD, Pfizer, and AstraZeneca. Faiez Zannad (Frankfurt/Main), Robert MacFadyen (Birmingham), received consultant honoraria and/or lecture fees from Giuseppe Mancia (Milan), David Morrow (Boston), Gun- Servier; AstraZeneca, Pfizer, Boehringer Ingelheim, Nov- nar Olsson (Mo¨lndal), Krishna Prasad (London), Zeljko artis, Abbott, Relypsa, Resmed, Merck, Daiichi Sankyo, Reiner (Zagreb), James Revkin (Ridgefiled), Edmond Takeda, Boston Scientific; Medtronic, and Otsuka.
Roland (Paris), Luis Ruilope (Madrid), Pierrre-Jean Tou-boul (Paris), Lars Wilhelmsen (Gothenburg), Faiez Zan- 1 Mancia G., De Backer G., Dominiczak A. et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of This workshop was supported by an unrestricted medical Cardiology (ESC). J. Hypertens. (2007) 25 1105–1187.
education grant from AstraZeneca. The initial drafts of 2 Mancia G., Laurent S., Agabiti-Rosei E. et al. Reappraisal of the manuscript were written by the authors. We thank European guidelines on hypertension management: a European Liz Anfield from Prime Medica Ltd, Knutsford, Cheshire, Society of Hypertension Task Force document. J. Hypertens.
who provided medical writing assistance funded by AstraZeneca. Employees of AstraZeneca were permitted 3 Graham I., Atar D., Borch-Johnsen K. et al. European guidelines to read the manuscript at a late stage in its development.
on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Responsibility for opinions, conclusions, and interpreta- Cardiology and other societies on cardiovascular disease tion of the data lies with the authors.
prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur. J. Cardiovasc. Prev.
Rehabil. (2007) 14(Suppl 2) S1–S113.
4 European Medicines Agency. Guideline on the evaluation of Jean Dallongeville received research grants from Astra- medicinal products for cardiovascular disease prevention. Lon- Zeneca, Sanofi-Aventis, and Pfizer; and consultant/ don: speaker for AstraZeneca, MSD, Sanofi-Aventis, Novartis ment_library/Scientific_guideline/2009/09/ WC500003290.pdf [accessed on 2010 July 19].
and Danone. Guy De Backer has received honoraria as a 5 Zannad F., Dallongeville J., Macfadyen R.J. et al. Prevention of speaker from AstraZeneca. Ian Graham received speaker cardiovascular disease guided by total risk estimation – chal- fees and unrestricted educational grants from Pfizer and lenges and opportunities for practical implementation: high- MSD. Wolfgang Koenig received research support grants lights of a CardioVascular Clinical Trialists (CVCT) Workshop of from Mercodia, Roche and Brahms; lecture fees from the ESC Working Group on CardioVascular Pharmacology and AstraZeneca, Merck, Sharp & Dohme, GlaxoSmithKline, Drug Therapy. Eur. J. Cardiovasc. Prev. Rehabil. (2011) (epub diaDexus, and Boehringer-Ingelheim; and consulting fees 6 Cooney M.T., Dudina A.L., Graham I.M. Value and limitations of from GlaxoSmithKline and Roche. Dr Koenig is a existing scores for the assessment of cardiovascular risk. A review member of the Steering Committee of the JUPITER trial.
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